CNVs conferring risk of autism or schizophrenia affect cognition in controls
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In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
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Stefansson et al. found a modest effect on verbal IQ (effect = 0.38, p = 0.033) and performance IQ (effect = 0.43, p = 0.018) from the 15q11.2 deletion.
“Stefansson et al. [38] found a modest effect on verbal IQ (effect = 0.38, p = 0.033) and performance IQ (effect = 0.43, p = 0.018) from the 15q11.2 deletion.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [38]
The best estimates of the population frequency of the 15q11.2 deletion range from 0.36% (UK BIOBANK) to 0.24% (Icelandic population).
“Currently, the best estimates range from 0.36% (UK BIOBANK)16 to 0.24% (Icelandic population).41”
From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [41]
The estimate of the effect of the 15q11.2 deletion on IQ is identical to the estimate measured in carriers in the general Icelandic population.
“This is identical to the estimate of the impact on IQ measured in carriers of the 15q11.2 deletion in the general Icelandic population41 and translates into a frequency of ID of 4.0% (compared with 2% in the general population).”
From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [41]
Rare, large-effect variants that increase risk for neurodevelopmental and neuropsychiatric disorders are also associated with deleterious effects on cognition, and ASD is no exception.
“Rare, large-effect variants that increase risk for neurodevelopmental and neuropsychiatric disorders are also associated with deleterious effects on cognition,28, 29, 30 and ASD is no exception.”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [28]
Penetrance of copy number variants can be highly variable, ranging from subtle effects detectable by neuropsychological tests to mild anxiety or ADHD to co-occurrence of severe psychiatric disorders.
“penetrance can be highly variable, ranging from subtle effects detectable by neuropsychological tests to mild degrees of anxiety/ADHD to co-occurrence of severe psychiatric disorders (Kendall et al., 2017; Stefansson et al., 2014; Ulfarsson et al., 2017)”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Stefansson et al., 2014
In population samples unselected for disease, many large-effect CNVs associated with ASD or SCZ have relatively modest effects on fertility compared with diagnosed individuals.
“Although some large effect CNVs associated with ASD or SCZ have effects on fecundity, when discovered in population surveys in individuals without regard to disease status, many have relatively modest effects on the ability to have offspring, compared with those having the disease diagnosis (Stefansson et al., 2014).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Stefansson et al., 2014
Estimates of selection based only on reproductive costs may underestimate selective pressure against schizophrenia-risk alleles because such alleles have multiple adverse effects, including rare CNVs that impair cognition and fecundity even without schizophrenia.
“estimates of selection (when based only on the reproductive costs of schizophrenia) may underestimate the actual selective pressure against such alleles given emerging evidence that such alleles have multiple adverse effects: for example, rare copy number variations (CNVs), implicated with penetrances ranging from 2–30% (the latter observed for 22q11.2 deletions), negatively impact cognition and F”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [7]
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- Authors
- Stefansson, H., Meyer-Lindenberg, A., Steinberg, S., Magnusdottir, B., Morgen, K., Arnarsdottir, S., Bjornsdottir, G., Walters, G. B., Jonsdottir, G. A., Doyle, O. M., Tost, H., Grimm, O., Kristjansdottir, S., Snorrason, H., Davidsdottir, S. R., Gudmundsson, L. J., Jonsson, G. F., Stefansdottir, B., Helgadottir, I., Haraldsson, M., Jonsdottir, B., Thygesen, J. H., Schwarz, A. J., Didriksen, M., Stensbøl, T. B., Brammer, M., Kapur, S., Halldorsson, J. G., Hreidarsson, S., Saemundsen, E., Sigurdsson, E., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- Heidelberg University (DE)
- King's College London (GB)
- National University Hospital of Iceland (IS)
- University of Iceland (IS)
- Sankt Hans Hospital (DK)
- Eli Lilly (United States) (US)
- Lundbeck (Denmark) (DK)
- ORCID
- Venue
- Nature
- Published
- 2013-12-18
- Volume
- 505
- Issue
- 7483
- Pages
- 361-366
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2103012833
- Cited by
- 699
- References
- 53
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 37 · 2023: 37 · 2022: 50 · 2021: 59 · 2020: 63 · 2019: 56 · 2018: 87 · 2017: 55 · 2016: 73 · 2015: 76 · 2014: 68 · 2013: 1
- FWCI
- 48.16
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion, other-oa)
- Funders
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- Lundbeckfonden (R155-2014-1724)
- Innovative Medicines Initiative
- FP7 People: Marie-Curie Actions
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- copy number variation, autism spectrum disorder, schizophrenia, fecundity, cognitive function, dyslexia, dyscalculia, brain structure, intellectual disability, Icelandic population, first-episode psychosis
- MeSH terms
- Adolescent, Adult, Aged, Autistic Disorder, Brain, Chromosome Deletion, Chromosomes, Human, Chromosomes, Human, Pair 15, Cognition, Dyslexia, Female, Fertility, Heterozygote, Humans, Iceland, Learning Disabilities, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Phenotype, Schizophrenia, Case-Control Studies, Genetic Predisposition to Disease, Young Adult, DNA Copy Number Variations
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